The field relates to compositions which are carboxymethyl reduced polysaccharides, and methods for use as plasma extenders and for coating iron oxide particles, and compositions comprised of superparamagnetic and non-superparamagnetic iron oxides coated with a reduced polysaccharide or derivatized reduced polysaccharide, and methods for use as MRI contrast agents and hematinics.
Since the invention of magnetic resonance imaging (MRI), a parallel technology of injectable chemicals called contrast agents has developed. Contrast agents play an important role in the practice of medicine in that they help produce more useful MRI images for diagnostic purposes. In particular, two classes of imaging agents have been developed and adopted in clinical practice. These are: low molecular weight gadolinium complexes such as Magnavist(copyright); and colloidal iron oxides. Neither of these two types of agents is ideal. Problems encountered with these agents are shown in Table 1, and include: expense of components; inefficiency of synthesis; loss of coating if sterilized by autoclaving; narrow range of organ uptake for purposes of imaging; side-effects; restriction of use to either first pass or equilibrium dosing; and others that are described herein. Agents that overcome these problems, and that combine the properties of these two types of contrast agents, are highly desirable.
An embodiment of the invention is a method of providing an iron oxide complex for administration to a mammal subject, the method comprising: producing a reduced polysaccharide iron oxide complex, and sterilizing the complex by autoclaving. In general, the reduced polysaccharide is a reduced polymer of glucose. An example of a reduced polymer of glucose is a reduced dextran. The reduced polysaccharide is produced through reaction of a polysaccharide with a reagent selected from the group consisting of a borohydride salt or hydrogen in the presence of a hydrogenation catalyst. In a further aspect of the method, the iron oxide is superparamagnetic.
Another preferred embodiment of the invention is a method of providing an iron oxide complex for administration to a mammalian subject, the method comprising: producing a derivatized reduced polysaccharide iron oxide complex, and sterilizing the complex by autoclaving. According to this method, producing the complex can include derivatizing a reduced polysaccharide by caboxyalkylation, for example, wherein the carboxyalkylation is a carboxymethylation. The term xe2x80x9cderivatizingxe2x80x9d and related terms (e.g. derivatives, derivatized, derivatization, etc) refer to the conventional sense of functionalization at the reactive sites of the composition. Further according to this method, the reduced polysaccharide can be a reduced dextran. The derivatized, reduced polysaccharide can be isolated as the sodium salt and does not contain an infrared absorption peak in the region of 1650-1800 cmxe2x88x921. In one aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 50xc2x0 C. In another aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 40xc2x0 C. In a further aspect of the method, the iron oxide is superparamagnetic.
In yet another embodiment, the invention provides a method of formulating an iron oxide complex coated with a reduced polysaccharide. This composition is for pharmacological use and the composition has decreased toxicity in comparison to an analogous iron oxide complex coated with native polysaccharide. The method of formulating such an iron oxide complex comprises: producing a reduced polysaccharide iron oxide complex, and sterilizing the complex by autoclaving. The formulation provides polysaccharide which was produced by reacting the polysaccharide with one of a reducing agent selected from the group consisting of a borohydride salt or hydrogen in the presence of an hydrogenation catalyst. The reduced polysaccharide iron oxide complex has such decreased toxicity. In a further aspect of the method, the iron oxide is superparamagnetic.
In yet another embodiment, the invention provides a method of formulating an iron oxide complex coated with a reduced derivatized polysaccharide. This composition is for pharmacological use and the composition has decreased toxicity in comparison to an analogous iron oxide complex coated with native derivatized polysaccharide. The method of formulating such an iron oxide complex comprises: producing a reduced derivatized polysaccharide iron oxide complex; and sterilizing the complex by autoclaving. According to this method, producing the complex can include derivatizing a reduced polysaccharide by carboxyalkylation, for example, wherein the carboxyalkylation is a carboxymethylation. Further according to this method, the reduced polysaccharide can be a reduced dextran. The derivatized, reduced polysaccharide can be isolated as the sodium salt and does not contain an infrared absorption peak in the region of 1650-1800 cmxe2x88x921. In one aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 50xc2x0 C. In another aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 40xc2x0 C. In a further aspect of the method, the iron oxide is superparamagnetic.
Another embodiment of the invention provides a reduced derivatized polysaccharide iron oxide complex with T1 and T2 relaxation properties to allow contrast agent signal enhancement with T1 sequences and signal diminishment with T2 sequences. A further aspect of the embodiment is that the reduced derivatized polysaccharide iron oxide can be administered multiple times for sequential imaging in a single examination. Yet another aspect of the agent is that it can be used to image multiple organ systems including the vascular system, liver, spleen, bone marrow, and lymph nodes.
Another embodiment of the invention provides a reduced polysaccharide iron oxide complex for use as an intravenous iron supplement.
Another embodiment of the invention provides a reduced derivatized polysaccharide iron oxide complex for use as an intravenous iron supplement.
In yet a further embodiment, the invention provides an improved method of administering to a mammalian subject an autoclaved reduced polysaccharide iron oxide complex. The improved method of administration comprising: injection of an autoclaved reduced polysaccharide iron oxide complex in a volume of 15 ml or less. In another aspect of the embodiment the injected volume is injected as a bolus. In a further aspect of the method, the iron oxide is superparamagnetic. In a further aspect of the embodiment the injected volume provides improved image quality.
In yet a further embodiment, the invention provides an improved method of administering to a mammalian subject an autoclaved derivatized reduced polysaccharide iron oxide complex. The improved method of administration comprising: injection of an autoclaved reduced derivatized polysaccharide iron oxide complex in a volume of 15 ml or less. In another aspect of the embodiment the injected volume is injected as a bolus. In a further aspect of the method, the iron oxide is superparamagnetic. In a further aspect of the embodiment the injected volume provides improved image quality.
An embodiment of the invention provides an improved method of administering to a mammalian subject a reduced polysaccharide iron complex in a manner that the composition provides reduced toxicity, wherein the improvement comprises utilizing a reduced polysaccharide in formulation of the composition. In a further aspect of the embodiment, the iron oxide is superparamagnetic.
An embodiment of the invention provides an improved method of administering to a mammalian subject a reduced derivatized polysaccharide iron complex in a manner that the composition provides reduced toxicity, wherein the improvement comprises utilizing a reduced derivatized polysaccharide in formulation of the composition. In a further aspect of the embodiment, the iron oxide is superparamagnetic.
An embodiment of the invention provides a reduced polysaccharide iron oxide complex, wherein the reduced polysaccharide is derivatized, for example, the reduced derivatized polysaccharide is a carboxyalkyl polysaccharide. The carboxyalkyl is selected from the group consisting of carboxymethyl, carboxyethyl and carboxypropyl. Further, the reduced polysaccharide can be a reduced dextran, for example, the reduced dextran can be a reduced carboxymethyl dextran. A further aspect of this embodiment of the invention is that the level of derivatization of the reduced dextran is at least 750 xcexcmole but less than 1500 xcexcmole of carboxyl groups per gram of polysaccharide wherein said composition has reduced toxicity relative to composition with respect to lower levels of derivatization.
An embodiment of the invention provides a reduced polysaccharide iron oxide complex, such complex being stable at a temperature of at least approximately 100xc2x0 C. In a preferred embodiment, such complex is stable at a temperature of approximately 121xc2x0 C. In an even more preferred aspect of the reduced polysaccharide iron oxide complex, such complex is stable at a temperature of at least 121xc2x0 C. for a time sufficient to sterilize the complex. In a further aspect of the embodiment, the iron oxide is superparamagnetic.
An embodiment of the invention provides a reduced derivatized polysaccharide iron oxide complex, such complex being stable at a temperature of at least approximately 100xc2x0 C. In a preferred embodiment, such complex is stable at a temperature of approximately 121xc2x0 C. In an even more preferred aspect of the reduced polysaccharide iron oxide complex, such complex is stable at a temperature of at least 121xc2x0 C. for a time sufficient to sterilize the complex. In a further aspect of the embodiment, the iron oxide is superparamagnetic.
A preferred embodiment of the invention is a method of formulating for pharmacological use a reduced polysaccharide iron oxide complex having increased pH stability in comparison to the corresponding native dextran iron oxide, the method comprising: providing dextran; and reacting the dextran with a borohydride salt or hydrogen in the presence of an hydrogenation catalyst, reacting the reduced dextran with iron salts to provide a formulation having a stable pH.
A preferred embodiment of the invention is a method of formulating for pharmacological use a reduced derivatized polysaccharide iron oxide complex having increased pH stability in comparison to the corresponding native dextran iron oxide, the method comprising: providing dextran; and reacting the dextran with a borohydride salt or hydrogen in the presence of an hydrogenation catalyst, reacting the reduced dextran with iron salts to provide a formulation having a stable pH.
In another embodiment, the invention provides a method of formulating a reduced derivatized dextran composition for pharmacological use wherein the composition has decreased toxicity in comparison to native dextran; comprising: producing a reduced derivatized polysaccharide; and sterilizing the product by autoclaving. According to this method, the reduced polysaccharide is obtained by reacting the native polysaccharide with one of several reducing agents selected from the group consisting of a borohydride salt, or hydrogen in the presence of a hydrogenation catalyst. In a preferred aspect of the embodiment the polysaccharide is dextran. Producing the composition can include derivatizing a reduced polysaccharide by carboxyalkylation, for example, wherein the carboxyalkylation is a carboxymethylation. Further according to this method, the reduced polysaccharide can be a reduced dextran. The derivatized, reduced polysaccharide can be isolated as the sodium salt and does not contain an infrared absorption peak in the region of 1650-1800 cmxe2x88x921. In one aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 50xc2x0 C. In another aspect of the method, producing the derivatized reduced polysaccharide is achieved at a temperature of less than approximately 40xc2x0 C.
An embodiment of the invention provides an improved method of administering to a mammalian subject a reduced derivatized polysaccharide in a manner that the composition provides reduced toxicity, wherein the improvement comprises utilizing a reduced polysaccharide in formulation of the composition.
An embodiment of the invention provides a reduced polysaccharide, wherein the reduced polysaccharide is derivatized, for example, the reduced derivatized polysaccharide is a carboxyalkyl polysaccharide. The carboxyalkyl is selected from the group consisting of carboxymethyl, carboxyethyl and carboxypropyl. Further, the reduced polysaccharide can be a reduced dextran. A further aspect of this embodiment of the invention is that the level of derivatization of the reduced dextran is at least 750 micromolar of carboxyl groups per gram of polysaccharide wherein said composition has reduced toxicity relative to composition with lower levels of derivatization.
Another embodiment of the invention is a method of formulating a dextran composition for pharmacological use and having decreased toxicity in comparison to native dextran, the method comprising: providing dextran; and reacting the provided dextran with a borohydride salt or hydrogen in the presence of an hydrogenation catalyst followed by carboxymethylation, the reduced carboxymethylated dextran having decreased toxicity.
Another embodiment of the invention is an improved method of administering to a mammalian subject a polysaccharide composition of the type wherein the composition includes dextran in a manner that the composition provides reduced toxicity, wherein the improvement comprises utilizing reduced carboxymethylated dextran in lieu of dextran in the formulation. In another aspect, an embodiment of the invention is an improved method of administering to a mammalian subject a polysaccharide in a manner that the composition provides reduced toxicity, wherein the improvement comprises utilizing a reduced carboxymethylated polysaccharide in formulation of the composition.
An embodiment of the invention provides a method of use of reduced derivatized dextrans as blood expanders.